Surfactants (surface active agents, also referred to as tensides) are ubiquitous, and used in products and applications where it is necessary to decrease the surface tension between two immiscible phases, or where it is necessary to increase the solubility of one phase in the other. Normally, one of the phases consists of water or a water-rich mixture (the aqueous phase), whereas the other consists of a liquid or solid phase (the oily phase) that is, by itself, immiscible or poorly soluble in water. Surfactants perform their action by adsorbing to the interface between the aqueous and oily phase, and/or by spontaneously forming aggregates (e.g. liquid crystals or micelles). In order to do so, it is necessary that the surfactant molecule consists of two separate, but linked moieties; a hydrophilic moiety that is soluble in water (the “head-group”), and a hydrophobic moiety, that is soluble in oil (the “tail”). This dual nature of the molecule is referred to as amphiphilicity. The amphiphilic character of the surfactant molecule means that the hydrophilic part will prefer to dwell in the aqueous phase, whereas the hydrophobic part will prefer the oily phase. Consequently, the surfactant as a whole will prefer to reside at the interface between the aqueous and the oily phase, hence decreasing the surface tension between the two phases and facilitating mixing (dispersing) of one phase in the other. Another effect of the surfactant amphiphilicity is its capacity to spontaneously form aggregates. In aqueous solution, soluble surfactants thus spontaneously form aggregates, micelles, where the hydrophobic moieties are directed inwards, away from the aqueous phase, whereas the hydrophilic moieties are directed outwards, towards the aqueous phase. As a consequence, an oily substance can be incorporated in the interior, hydrophobic part of the micelles, hence increasing its solubility. This process is referred to as solubilisation, and the lowest surfactant concentration at which micelles form is referred to as the critical micelle concentration (CMC). The CMC is an important characteristic of a surfactant. Above the CMC all additional surfactants added to the system go to micelles. Before reaching the CMC, the surface tension changes strongly with the concentration of the surfactant. After reaching the CMC, the surface tension remains relatively constant or changes with a lower slope. The value of the CMC for a given agent in a given medium depends on temperature, pressure, and on the presence and concentration of other surface active substances and electrolytes. Another important characteristic of a surfactant is the so-called Krafft temperature. The Krafft temperature is defined as the temperature at which the surfactant concentration of the saturated surfactant solution equals CMC. Consequently, at temperatures below the Krafft temperature, the surfactant solubility is very low and the surfactant behaves as a regular organic molecule. At the Krafft temperature the solubility increases dramatically, micelles form and the surface active properties of the surfactant manifest themselves in a useful manner. At temperatures below the Krafft temperature, on the other hand, the solubility of the surfactant is so low that the surfactant is practically useless in many applications. As will be elaborated on below, most applications therefore require surfactants with Krafft points below room temperature, since products containing surfactants are generally intended for use under everyday conditions.
Both CMC and Krafft temperature depend directly on surfactant structure. Keeping other molecular properties constant, increasing alkyl chain length decreases CMC and favors surfactant adsorption, whereas increasing head-group length decreases the Krafft temperature. This dependence has direct practical consequences for surfactant selection and design. As already described, it is of utmost importance to identify a surfactant that has a Krafft point well below the temperature to which the product will be subjected under actual use (normally room temperature). On the other hand, a long alkyl-chain promotes adsorption and aggregation, so that a smaller concentration of surfactant is required to achieve a given effect. Consequently, a combination of a long alkyl chain with a long head-group is often beneficial for surfactant functionality.
The molecular characteristics of a given surfactant also directly impact its interactions with cells and mucosa, and hence its toxicological properties. In this respect it is important to note that an inherent drawback of the amphiphilic nature of surfactants is their tendency to adsorb to mucosal surfaces and other biointerfaces, as well as to incorporate themselves into cell membranes. Studies show that the toxicity towards aquatic model organisms decreases with decreasing surface activity and increasing size of the head-group[18,19]. These conclusions have been shown to hold true also in human cell models[1]. Furthermore, the studies in human cell models have revealed that a long alkyl chain is also, in itself, beneficial in terms of biocompatibility. Consequently, the combination of a long alkyl chain with a long head-group is beneficial also in terms of toxicity. In more general terms, the toxicological profile of non-ionic (charge-neutral) surfactants are superior as compared with anionic surfactants, which, in turn, are superior over cationic ones[18,19]. For many applications that require high biocompatibility, non-ionic surfactants are therefore the prime choice.
In addition to the aspects pertaining to acute toxicity, the overall environmental impact of a surfactant is also an important factor to consider when comparing different surfactants. Both the properties of the surfactant itself, such as biodegradability, and the properties of the manufacturing process, e.g. the nature of the starting materials, must be considered.
The amphiphilic nature of surfactants makes them act as detergents, wetting agents, emulsifiers, dispersants etc. Surfactants are therefore used in manifold applications, e.g. pharmaceutics, food, paint, adhesives, personal care products, cosmetics, laundry and also for more specialised applications like membrane protein solubilisation.
Dispersions of solid particles in a liquid aqueous medium are normally referred to as suspensions or sols. Such systems are essential in many applications, e.g. pigment particles in paints, and sun-blocking particles in creams and lotions for cosmetic use. In order to properly wet and disperse the particles in suspensions a surfactant is generally required in order to decrease the surface tension between the particle and the continuous medium. Similarly, proper dispersion of a liquid oily phase in water (or dispersion of water in oil) is referred to as emulsification. Again, examples of emulsions include paint and cosmetic preparations.
In the field of pharmaceutics, surfactants are used for e.g. suspension of hydrophobic drug particles in aqueous media, for instance in liquids for inhalation (pulmonary nebulisation and nasal sprays); emulsification of oily drugs in aqueous vehicle, for instance in creams and lotions containing pain-killers; and for inhibition of protein and peptide adsorption and aggregation in liquid formulations for injection and inhalation.
A particularly challenging application is pharmaceutics intended for pulmonary and nasal inhalation (liquids for nebulisation and nasal sprays). In order to have its desired effect, the drug particles in inhaled medications need to be micronised, i.e. milled to a size of a few microns. As a result of the small particle size, the powder becomes extremely cohesive and difficult to disperse. In addition, the drug particles are often very hydrophobic and therefore difficult to wet. As a consequence of these features, aggregation (i.e. formation of larger, composite particles, composed of primary particles) is often encountered. Aggregation is detrimental to product performance, since larger particles do not reach the deep parts of the pulmonary tract, due to impaction and concomitant retention in airway bifurcations. Due to the challenging demands on formulations for inhalation, it is generally true that a formulation concept that works in the area of inhalation also works in other, less challenging pharmaceutical areas, such as dispersion of solid particles in topical creams and lotions as well as injectabilia.
Preferably, a surfactant is chemically stable, i.e. does not readily degrade under the intended product shelf life and does not induce degradation of other components in the formulation. This is especially important for pharmaceutics, cosmetics and food, where a strict minimisation of degradents is desirable for reason of safety and product performance.
Today, the field of non-ionic surfactants is completely dominated by substances based on the use of polyethyleneglycole (PEG, also referred to as polyethyleneoxide, PEO) as hydrophilic head-group. In simple PEG-chain surfactants, the PEG chain may be attached to the hydrophobic moiety of the surfactant (the alkyl chain) trough an ester bond (e.g. Solutol™ and the Myrj™ family of surfactants) or an ether bond (e.g. the Brij™ family of surfactants). More complex PEG-based surfactants include the well-known family of ethoxylated sorbitan esters known as polysorbates (or Tween™), amphiphilic co-polymers of PEG and poly(propylene oxide) (e.g. Pluronics™), and ethoxylated triglycerides (e.g. Cremophor™). Polysorbate is of particular interest, since it is the only surfactant currently approved for all pharmaceutical administration forms.
In spite of the fact that they are produced and used on an enormous scale, all surfactants based on PEG share a number of substantial drawbacks, namely formation of toxic degradation products in aqueous systems (e.g. formaldehyde, formic acid and acetaldehyde); chemical instability and generation of oxidising peroxo radicals having a detrimental effect on product stability; polydispersity and batch variability[2-5]. Furthermore, the temperature-sensitivity of aqueous solutions (phase separation, clouding, emulsification failure) is a problem in processes that involve heat, such as e.g. sterilisation by means of autoclavation[6]. In addition, most PEG-based surfactants have petrochemical origin, thus not originating from renewable sources, which is important when considering the environmental impact of a surfactant.
Another group of non-ionic surfactants are the alkylglycosides, also named alkylpolyglucosides, which are non-ionic surfactants derived from saccharides (sugars). These surfactants have been found to be compatible with skin and mucosa and to be non-toxic in acute and repeated dose toxicity studies[20]. Glycosides are substituted saccharides in which the substituent group is attached, through an oxygen atom, to an aldehyde or ketone carbon. Accordingly, glycosides are considered acetals. As with the term “saccharide”, the term “glycoside” defines neither the number nor the identity of the saccharide units in the molecule. A common shorthand nomenclature applied to alkylglycosides is CnGm, where n is defined as the number of carbon atoms in the alkyl chain and m the number of saccharide units (normally glucose units) comprising the head group.
Alkylglycosides are known to be effective as surfactants in detergents and they exhibit solubilizing properties. In addition, alkylglycosides have a favourable biodegradability, with degradation products being an alcohol or fatty acid and an oligosaccharide[23]. In contrast to the PEG-based surfactants they are stable towards hydrolysis and autoxidation in aqueous systems, and do not give rise to toxic degradation products, Hence, they have found use in many applications where they come in contact with the human body, such as cosmetics and personal care products. Examples of alkylglycosides used today in these applications are EcoSense 1200 (alkylpoly glucoside C12-14) and EcoSense 919 (alkylpoly glucoside C8-16) from Dow Chemicals, Plantaren (decyl glucoside), Plantapon LGC Sorb (sodium lauryl glucose carboxylate), Plantasol CCG (caprylyl capryl glucoside) from Cognis, and TEGO Care CG90 (C16-C18 glucoside) from Evonik, etc. In the pharmaceutical field, Aegis Therapeutics has recently developed technologies primarily utilizing C14G2 for enhancement of the physical stability and bioavailability of peptides and proteins[21,22].
Ways to produce alkylglycosides have previously been disclosed[8,9,10].
Conventional, commercially available alkylglycosides, such as those mentioned in the preceding paragraph, address many of the issues related to PEG-based surfactants, but still have a number of drawbacks. Conventional Fischer synthesis, used for the industrial production of these alkylglycosides, yields a polydisperse mixture of alkylglycosides having only 1-3 repeating sugar units[7]. With such short head-groups, it is not possible to extend the length of the tail without risking problems related to high Krafft points and concomitant issues related to poor solubility. As already described, the toxicity of a surfactant also increases with shorter head-group. Hence, there is a need for a new type of surfactant that addresses these issues.